Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation.
BACKGROUND
A massive destruction of transplanted tissue occurs immediately following transplantation of pancreatic islets from pig to non-human primates. The detrimental instant blood-mediated inflammatory reaction (IBMIR), triggered by the porcine islets, is a likely explanation for this tissue loss. This reaction may also be responsible for mediating an adaptive immune response in the recipient that requires a heavy immunosuppressive regimen.


METHODS
Low molecular weight dextran sulfate (LMW-DS) and the complement inhibitor Compstatin were used in a combination of in vitro and in vivo studies designed to dissect the xenogeneic IBMIR in a non-human primate model of pancreatic islet transplantation. Adult porcine islets (10,000 IEQs/kg) were transplanted intraportally into three pairs of cynomolgus monkeys that had been treated with LMW-DS or heparin (control), and the effects on the IBMIR were characterized. Porcine islets were also incubated in human blood plasma in vitro to assess complement inhibition by LMW-DS and Compstatin.


RESULTS
Morphological scoring and immunohistochemical staining revealed that the severe islet destruction and macrophage, neutrophilic granulocyte, and T-cell infiltration observed in the control (heparin-treated) animals were abrogated in the LMW-DS-treated monkeys. Both coagulation and complement activation were significantly reduced in monkeys treated with LMW-DS, but IgM and complement fragments were still found on the islet surface. This residual complement activation could be inhibited by Compstatin in vitro.


CONCLUSIONS
The xenogeneic IBMIR in this non-human primate model is characterized by an immediate binding of antibodies that triggers deleterious complement activation and a subsequent clotting reaction that leads to further complement activation. The effectiveness of LMW-DS (in vivo and in vitro) and Compstatin (in vitro) in inhibiting this IBMIR provides the basis for a protocol that can be used to abrogate the IBMIR in pig-human clinical islet transplantation.
Goto
Masafumi
M
Tohoku University International Advanced Research and Education Organization, Tohoku University, Sendai, Japan.
Tjernberg
Jenny
J
Dufrane
Denis
D
Elgue
Graciela
G
Brandhorst
Daniel
D
Ekdahl
Kristina Nilsson
KN
Brandhorst
Heidi
H
Wennberg
Lars
L
Kurokawa
Yoshimochi
Y
Satomi
Susumu
S
Lambris
John D
JD
Gianello
Pierre
P
Korsgren
Olle
O
Nilsson
Bo
B
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000008:administration & dosage; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000097:blood* / Q000209:etiology*; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects* / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D008252:Macaca fascicularis; D010456:Peptides, Cyclic / Q000008:administration & dosage; D034421:Sus scrofa; D014183:Transplantation, Heterologous
D016207:Cytokines; D010456:Peptides, Cyclic; C111828:compstatin; D006493:Heparin; D016264:Dextran Sulfate